A previously healthy, fully vaccinated 21-month-old female presented to an outside hospital with acute bilateral facial twitching, tongue fasciculations, and confusion without fever. Initial CSF showed mild pleocytosis (WBC 17/uL; lymphocytes 94%; protein 33mg/dL; glucose 51mg/dL). MRI revealed bilateral periolandic diffusion restriction and thalamic T2/FLAIR hyperintensity, concerning for autoimmune encephalitis (AE), infection, or genetic/metabolic encephalopathy. Multiplex syndromic panel (BioFire) and CSF mNGS (Mayo) were both negative for HSV, without dedicated HSV PCR performed. Presumed AE was treated with IVIG and pulse steroids, and later plasma exchange. Empiric acyclovir was discontinued after negative CSF studies for HSV.

Following clinical and radiographic progression, the patient was transferred to UCSF on hospital day 14. mNGS (Delve Bio) on CSF collected 16 days after initial presentation identified HSV-1 (4,889 unique reads, 19M total reads, 88.1% genome coverage), subsequently confirmed by dedicated HSV PCR. Her clinical course was most consistent with primary HSV infection with possible secondary AE. She was treated with a 21-day course of acyclovir and plasma exchange, then transitioned to suppressive therapy after documented negative CSF HSV PCR, with gradual clinical improvement.